The long term goal of this work is to elucidate the underlying molecular mechanisms leading to the development of neurofibrillary tangles (NFTs), a hallmark pathological feature of Alzheimer's disease. The investigators will focus on the microtubule associated protein, tau, known to be the major molecular component of NFTs. Whereas normal tau is capable of interacting directly with microtubules and regulating their dynamics and stability, the abnormal tau found in NFTs is unable to bind microtubules concomitant with altered structural and functional properties. This project is designed to determine the molecular and structural features of normal tau action, which will be critical information in the quest to understand abnormal tau behavior. The applicants' strategy will be to integrate two laboratories with expertise in two extremely complementary approaches - molecular biology and Xray crystallography. The goals are to identify critical domains of tau and tubulin involved in their binding interaction, to determine the mechanistic capabilities of each microtubule binding domain of tau, and to determine the three dimensional structure of tau functional domains, alone and in association with their cognate tubulin sites. Taken together, achieving these goals will represent a major step forward in gaining a detailed mechanistic understanding of normal and abnormal tau action and a structure based understanding of the biochemistry of NFTs, a critical prerequisite for the development of rational therapies to address the problem of NFT formation.